《Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design》 was written by Cheng, Hengmiao; Li, Chunze; Bailey, Simon; Baxi, Sangita M.; Goulet, Lance; Guo, Lisa; Hoffman, Jacqui; Jiang, Ying; Johnson, Theodore Otto; Johnson, Ted W.; Knighton, Daniel R.; Li, John; Liu, Kevin K.-C.; Liu, Zhengyu; Marx, Matthew A.; Walls, Marlena; Wells, Peter A.; Yin, Min-Jean; Zhu, Jinjiang; Zientek, Michael. Category: pyridine-derivativesThis research focused ontricyclic imidazonaphthyridine preparation PI3K mTOR dual kinase inhibitor; PF-04979064; PI3K/mTOR dual inhibitor; aldehyde oxidase metabolism; antitumor; cancer; kinase inhibitor. The article conveys some information:
PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncol. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clin. trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and phys. properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064 (I). This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P 450 and aldehyde oxidase (AO), poor permeability, and poor solubility An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates. In the experiment, the researchers used many compounds, for example, 6-Bromopyridin-3-amine(cas: 13534-97-9Category: pyridine-derivatives)
6-Bromopyridin-3-amine(cas: 13534-97-9) belongs to anime. Milder oxidation, using reagents such as NaOCl, can remove four hydrogen atoms from primary amines of the type RCH2NH2 to form nitriles (R―C≡N), and oxidation with reagents such as MnO2 can remove two hydrogen atoms from secondary amines (R2CH―NHR′) to form imines (R2C=NR′). Tertiary amines can be oxidized to enamines (R2C=CHNR2) by a variety of reagents.Category: pyridine-derivatives